Anti-angiogenesis has emerged as a major new approach to breast cancer therapy. Exploration of the VEGF/VEGF receptor pathway has defined a paradigm whereby the discovery of a novel and crucial family of endothelial receptors has led to the development of rational inhibitors of tumor angiogenesis. In the first phase of Project 6, we have established that another novel endothelial receptor, Tie-2, is also crucial for the development of the tumor vasculature and, therefore, will be an important new candidate as a target for the development of the tumor vasculature and, therefore, will be an important new candidate as a target for the development of anti-angiogenic therapeutics. Based on these results, the principal goal of the new aims for Project 6 is to push hard to develop clinically relevant approaches to the formulation and delivery of anti- angiogenic agents targeting the Tie-2 pathway. In anticipation of developing anti-Tie-2 inhibitors as therapeutic agents, a secondary goal will be to develop strategies to monitor the efficacy of anti-angiogenic agents. To acheive these goals, the following three Specific Aims have been developed. Specific Aim 1. Develop biomarkers of active angiogenesis. Specific Aim 2. Determine the efficacy of blocking tumor angiogenesis using systemic delivery of recombinant, soluble Tie-2. Specific Aim 3. Develop small molecule inhibitors of Tie-2 as an affinity target. Successful completion of these aims will result in the development of novel and clinically useful anti-angiogenic agents and, hopefully, in the development of approaches to measure the efficacy of these agents in clinical trials.